Parkinson's Pharmacotherapy

Original Editor - Andrew Bennett Lee Price Top Contributors - Lucinda hampton, Kim Jackson, Lauren Lopez, Mariam Hashem, Andrew Bennett Lee Price, Aminat Abolade, Tony Lowe, Nicole Bailey and Stacy Schiurring

Introduction to Parkinson's Pharmacotherapy

Parkinson's disease (PD) represents one of the most prevalent neurodegenerative disorders worldwide, affecting millions of individuals and presenting significant challenges for patients, families, and healthcare professionals alike. Whilst the underlying pathophysiology remains incompletely understood, the characteristic loss of dopaminergic neurons in the substantia nigra has led to the development of various pharmacological interventions aimed at restoring dopamine function within the basal ganglia. For rehabilitation professionals working with people with Parkinson's (pwP), understanding the complex landscape of parkinsonian medicines is essential for optimising rehabilitation outcomes, as these treatments directly influence motor function, cognitive performance, and overall quality of life.

The video below outlines briefly medication rational and major drug types

Deep brain stimulation, stem cell therapy and gene therapy are alternative approaches that aim to lower the need to medications.

This article examines the current pharmacological approaches to Parkinson's symptom management, exploring the mechanisms of action, clinical applications, and side effect profiles of the primary drug classes used in contemporary practice. By developing a thorough understanding of how these medicines affect both movement and non-motor symptoms, rehabilitation professionals can better tailor their interventions, anticipate treatment-related fluctuations, and collaborate effectively within the multidisciplinary team to enhance patient care and therapeutic outcomes.

Common Medications in the Management of Parkinson's

The most common and effective medication for PD management is levodopa, often combined with carbidopa, in fixed-dose combinations such as co-careldopa (Sinemet) or co-beneldopa (Madopar).

Levodopa is a precursor to dopamine, a neurotransmitter that is progressively depleted in the brains of pwP due to the loss of dopaminergic neurons in the substantia nigra. Unlike dopamine itself, levodopa can cross the blood-brain barrier, where it is subsequently converted to dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC).

Carbidopa serves as a peripheral decarboxylase inhibitor, preventing the premature conversion of levodopa to dopamine outside the brain. This mechanism ensures that more levodopa reaches the central nervous system whilst simultaneously reducing peripheral side effects such as nausea, vomiting, and cardiovascular complications that would otherwise occur from dopamine production in peripheral tissues. The combination therapy typically demonstrates superior efficacy and tolerability compared to levodopa monotherapy.

Other Essential Parkinson's Medications include:

Dopamine agonists directly stimulate dopamine receptors in the brain, mimicking the action of naturally occurring dopamine. These medicines are particularly valuable in younger patients and early-stage disease, as they may delay the need for levodopa therapy and potentially reduce the risk of developing motor complications such as dyskinesias and motor fluctuations. In general, dopamine agonists are not as potent as carbidopa/levodopa and may be less likely to cause dyskinesias. Commonly used examples include Pramipexole (Mirapex®), Pramipexole Dihydrochloride Extended-Release (Mirapex ER®), Ropinirole (Requip®), Ropinirole Extended-Release Tablets (Requip® XL™). The main adverse effects seen after the intake of this medication include somnolence, withdrawal, and psychiatric disorders, such as confusion and hallucinations. It is vital that the physical therapist is aware of such side effects to dictate the treatment.

MAO-B inhibitors (monoamine oxidase type B inhibitors) work by blocking the enzyme responsible for breaking down dopamine in the brain, thereby prolonging the action of both endogenous and therapeutically administered dopamine. These agents can be used as monotherapy in early disease or as adjunctive therapy alongside levodopa. Commonly used MAO-B inhibitors include selegiline (Deprenyl, Eldepryl, Zelapar) and rasagiline (Azilect). More recently, the drug safinamide (Xadago) was also approved for use in PD, which appears to have multiple modes of action, one of which is thought to be inhibition of MAO-B . MAO-B inhibitors are generally well tolerated, with gastrointestinal side effects being the most common problem. Other adverse effects include aching joints, depression, fatigue, dry mouth, insomnia, dizziness, confusion, nightmares, hallucinations, flu-like symptoms, indigestion, and headache.

COMT inhibitors (catechol-O-methyltransferase inhibitors) block another enzyme involved in dopamine metabolism, specifically extending the duration of action of levodopa by preventing its breakdown in both peripheral tissues and the brain. These are primarily used as add-on therapy to levodopa combinations. Examples of COMT inhibitors include entacapone (Comtan), tolcapone (Tasmar), and opicapone (Ongentys).

Amantadine possesses multiple mechanisms of action, including NMDA receptor antagonism, dopamine reuptake inhibition, and anticholinergic effects. It is particularly useful for managing levodopa-induced dyskinesias in advanced PD, though it also provides modest symptomatic benefit in early disease. Immediate-release amantadine is a mild agent that is used in early and advanced PD to help tremor. In recent years, amantadine has also been found useful in reducing dyskinesia that occur with dopamine medication. In 2017, an extended-release form of amantadine (Gocovri) was the first drug approved by the FDA specifically to treat dyskinesia in Parkinson's.

Anticholinergics reduce acetylcholine activity by acting as muscarinic receptor antagonists. They work by restoring the dopamine-acetylcholine balance that is disrupted when dopaminergic neurons are lost in Parkinson's disease. Whilst their role is now limited and they are prescribed infrequently, anticholinergics may offer some benefit in improving rigidity and tremor in PD, particularly resting tremor in younger patients (typically under 70 years). They have minimal effect on bradykinesia or postural instability. They are generally avoided in elderly patients or those with cognitive problems, due to an increased risk of confusion with this class of drugs. Examples of anticholinergics include benztropine, orphenadrine, procyclidine, and trihexyphenidyl (Benzhexol). Common adverse effects of anticholinergic drugs include memory problems, drowsiness, constipation, sedation, urinary retention, blurred vision, tachycardia, and delirium. Increased side effects are typically seen in the elderly, when compared with younger adults.

Rehabilitation Considerations of PD Medications

The selection and timing of these medications require careful consideration of individual patient factors, including age, symptom severity, cognitive status, and quality of life impact, with treatment decisions typically made collaboratively between the patient and specialist movement disorder teams.

Optimal timing of rehabilitation sessions in relation to PD medication is crucial for maximising therapeutic outcomes and patient safety. Rehabilitation treatment should be administered during the peak effective time of each individual medication, typically 30-90 minutes after levodopa administration when patients are in their "ON" state and experiencing optimal motor function. "Off" periods—when medication effects wear off and symptoms return or worsen—can occur unpredictably throughout the day, either between scheduled doses ("wearing off") or in the morning before the first dose. Recent advances in medication delivery, including continuous subcutaneous infusions approved in 2024 and on-demand treatments with 10-20 minute onset times, are helping to reduce these fluctuations.

Rehabilitation professionals should collaborate with patients to identify their individual medication patterns, schedule sessions during optimal "ON" periods, and remain flexible to accommodate unpredictable "OFF" episodes. Assessment of motor function, safety considerations, and treatment goals should all be adjusted based on the patient's current medication state, with recent systematic reviews emphasising that timing, frequency, and duration of physical therapy interventions significantly impact outcomes in Parkinson's disease. Understanding these medication dynamics allows rehabilitation professionals to provide more effective, personalised care whilst ensuring patient safety during rehabilitation activities.